The present invention relates generally to the iron binding protein lactoferrin. In particular, it relates to the use of lactoferrin to treat or prevent insult-induced metabolic imbalance in humans and animals, and its use for the manufacture of a medicament for the treatment or prevention of insult-induced metabolic imbalance in humans and animals.
Homeostasis is a state of equilibrium in the internal environment. The integrity of such system is continuously disturbed by stimuli that tend to create an internal imbalance. In response to prolonged stimuli, the compensatory mechanisms often do not restore the balance. This may, consequently lead to the activation of self-perpetuating, autodestructive mechanisms including death. The central pathway involved in the insult-induced metabolic imbalance may depend in part on the nature of the stimuli, but the hypo- or hyper-thermia appears to be common for many forms of insult. The energy balance of the internal environment is controlled by the central nervous system (CNS) and regulated by the decrease (chills) or increase (fever) of our body temperature. Whether the insult is microbial infection, inflammation or trauma the internal environment responds to those insults by activating thermoregulatory mechanisms that coincide with the production and release of many immunomodulatory substances. Cytokines, prostaglandins, and different growth factors and hormones are released from specific cells to restore the internal metabolic balance, which largely depends on the energy equilibrium.
The significance of lactoferrin in health and disease has been the subject of several reviews. A most recent publication entitled xe2x80x9cLactoferrin: Molecular Structure and Biological Functionxe2x80x9d has been published in 1995 by B. Lonnerdal and S. Iyer in Ann. Rev. Nutr., 15:93-110.
Lactoferrin is a multifunctional protein expressed in a variety of cell types under different mechanisms of control. The primary function of lactoferrin seems to be a protection against pathogenic bacteria. By virtue of sequestering iron, lactoferrin may control development of potential infections. In addition, it can kill a wide variety of Gram-negative and Gram-positive bacteria by direct interaction with the cell surface, a mode of action that is not dependent on iron. Lactoferrin is thought to be an important component of the defense system, active at mucosal surfaces, including the gastrointestinal tract. Various immunoregulatory and anti-infective roles for lactoferrin have been reviewed by J. Brock in an article entitled xe2x80x9cLactoferrin: a multifunctional immunoregulatory protein?xe2x80x9d and published in Immunology Today (1995), 16:417-419.
Although, considerable data from in vitro experiments indicate several physiological roles for lactoferrin, there is no firm evidence concerning its actual physiological function from in vivo studies. For example, in a review by Roy D. Byens and Werner R. Bezwoda entitled xe2x80x9cLactoferrin and the inflammatory responsexe2x80x9d and published in the book: Lactoferrin: Structure and Function, pp 133-141, (1994), a relationship between plasma lactoferrin and granulocyte activity in sepsis is mentioned. However, the biological function of the significant amounts of lactoferrin in plasma of septic patients is as yet incompletely understood.
In another review entitled xe2x80x9cThe role of lactoferrin as an anti-inflammatory moleculexe2x80x9d by Bradley E. Britigan, Jonathan S. Serody, and Myron S. Cohen and published in the book: Lactoferrin: Structure and Function, pp 143-156, (1994), the role of lactoferrin in inflammation is suggested to be played at two different levels: (i) as an antioxidant, capable of binding free iron, and (ii) as an endotoxin scavenger, capable of reducing lipopolysaccharide (LPS)-induced toxicity. Furthermore, the ability of lactoferrin to bind LPS in vitro has been confirmed by E. Elass-Rochard, A. Roseanu, D. Legrand, M. Trif, V. Salmon, C. Motas, J. Montreuil and G. Spik in an article entitled xe2x80x9cLactoferrin-lipopolysaccharide interaction: involvement of the 28-34 loop region of human lactoferrin in the high-affinity binding to Escheria coli 055B5 lipopolysaccharidexe2x80x9d, published in Biochem. J. (1995) 312:839-845. However, in vivo studies have to confirm lactoferrin""s role in those internal metabolic responses during inflammatory processes.
In another article entitled: xe2x80x9cLactoferrin can protect mice against a lethal dose of Escherichia coli in experimental infection in vivoxe2x80x9d by T. Zagulski, P. Lipinski, A. Zagulska, S. Broniek and Z. Jarzabek, published in 1989 in Br. J. Exp. Path., 79:697-704, the use of lactoferrin is disclosed to increase the survival of mice injected with a lethal dose of bacteria. However there is no disclosure that the intravenously administered lactoferrin has any effect on the gut function and structure to give such protection.
Relevant patents are also silent as to the role of lactoferrin in insult-induced metabolic activity.
U.S. Pat. No. 4,977,137 of Nichols et al. discloses milk lactoferrin as a dietary ingredient which promotes growth of the gastrointestinal tract of human infants and newborn nonhuman animals immediately on birth. Nichols discusses the use of lactoferrin in the management of short gut syndrome, an anatomical dysfunction rather than an insult-induced metabolic imbalance.
U.S. Pat. No. 5,240,909 of Nitsche relates to the use of lactoferrin as an agent for the prophylactic and therapeutic treatment of the toxic effects of endotoxins. Nitche discloses that the lactoferrin used according to his invention has the ability to neutralize endotoxin and must have bound to it either iron or another metal to be effective.
U.S. Pat. No. 5,066,491 of Stott et al. encompasses a method of disease treatment utilizing a therapeutically effective product produced from ordinary milk whey.
The method of the present invention provides a novel use of the iron binding protein lactoferrin to prevent or treat insult-induced metabolic imbalance in humans and other animals. In one embodiment of the present invention there is provided a method to use lactoferrin to modulate such metabolic imbalance through the gastrointestinal tract. In a further embodiment, the present invention relates to the use of lactoferrin for the manufacture of a medicament for the prevention or treatment of insult-induced metabolic imbalance in humans and animals. In yet a further embodiment, the present invention relates to the use of lactoferrin for the manufacture of a medicament for the modulation of such metabolic imbalance through the gastrointestinal tract.